Gestational Diabetes Mellitus Alters Placental Precursor mRNA Splicing.

UNLABELLED: Gestational diabetes mellitus (GDM) is defined as hyperglycemia first identified during pregnancy and can lead to adverse maternal and neonatal outcomes. The molecular mechanisms leading to these outcomes are currently poorly understood. While transcriptomics of GDM placentas has been previously studied, the effect on precursor mRNA splicing remains largely unknown. This study explores the impact of GDM on placental splicing and identifies its regulatory mechanisms. Using RNA sequencing data from Norwegian and Chinese cohorts, we uncovered thousands of differential splicing events. Pathway enrichment analysis revealed significant associations with metabolic and diabetes-related pathways. Splicing factor motif and cross-linking and immunoprecipitation sequencing analyses highlighted serine/arginine-rich splicing factor 10 (SRSF10) as a key regulator in this process, with its binding enriched at misspliced exons. Silencing SRSF10 in placental cells mirrored GDM-associated missplicing in key genes. These findings underscore splicing dysregulation as a critical process in GDM pathogenesis, suggesting that targeting SRSF10 could be a potential therapeutic approach to mitigate the deleterious effects of GDM.

ARTICLE HIGHLIGHTS: Gestational diabetes mellitus (GDM) causes hyperglycemia during pregnancy and adverse maternal and neonatal outcomes. Bulk placental gene expression has been reported largely unchanged. RNA sequencing of Norwegian and Chinese GDM placentas reveals hundreds of differential splicing events enriched for metabolic- and diabetes-related pathways. Motif enrichment and cross-linking and immunoprecipitation sequencing integration identify serine/arginine splicing factor 10 as a key regulator of GDM-associated missplicing. Silencing serine/arginine splicing factor 10 in placental models recapitulates the GDM-associated missplicing program.